Introduction Constantly, cells undergo destructive oxidative stress processes, which could originate either from exogenous or endogenous sources. Cells withstand this occurrence through engaging several distinct defense mechanisms ranging from free radical scavengers such as glutathione (GSH), vitamins C, and antioxidant enzymes to the elaborate DNA repair systems (1). Genetic alterations to the DNA both in somatic and germ cells can induce a plethora of events, from single-point mutations to chromosomal break, rearrangements or loss, which finally lead to several genetic-related diseases among which is also cancer (2). In order to identify genotoxic molecules, researchers perform specified assays contributing DNA damage in toxically affected cells. Loss of excision repair, cross-linking, alkali-labile sites, point mutations, structural and numerical chromosomal aberrations, and the compromised integrity of the genetic material have been known as the leading Abstract Ziziphus jujuba Mill (ZJ), which has been extensively used by the Iranian traditional healers, belongs to the Ramnaceae family. This semitropical herb contains large quantities of polyphenols and flavonoids, which in turn reveal antioxidant, antibacterial, free radical scavengering, and several other pharmacological activities. The purpose of the present study was to evaluate the DNA damage prevention potential of hydroalcoholic and polyphenolic extracts of Ziziphus jujuba on HepG2 cells. Throughout the assessment of genoprotective properties, cells were incubated with various concentrations of hydroalcoholic (0.1, 1, 10, and 50 µg/ml) and polyphenolic extracts (0.1 and 1 µg/ml) for a one-hour period, followed by a one-hour incubation period with genotoxic concentration of methyl methanesulfonate (MMS) (10 µM). The comet assay method was applied because of its being attributable to the substantial sensitivity, its inexpensiveness, and its straightforward procedure of use. The tail length, percentage of DNA in tail, and tail moment were measured. Statistical analysis revealed that concentrations of 10 μg/ml for hydroalcoholic extract and 1μg/ml for polyphenolic extract were genoprotective against MMS. Therefore, our results suggest that Ziziphus jujuba at suitable doses can prevent DNA damage.